Process for resolution of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole and compounds therefor

ABSTRACT

A process for resolving or enriching (R,S) 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (pramipexole) into optical isomers uses a monovalent salt thereof, e.g. pramipexole monohydrochloride, as a substrate. The monovalent salt is treated with an optically active acid, e.g. with L(+)-tartaric acid, to yield a diastereomeric mixed salt. The mixed salt is subjected to fractional crystallization to yield an optically enriched mixed salt. The mixed salt can be treated with base to liberate the desired isomer of pramipexole.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for the resolution of(R,S) 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole intooptically enriched and/or optically pure enantiomers and to compoundsuseful therein.

[0002] 2-amino-6-(substituted)amino-4,5,6,7-tetrahydrobenzothiazoleshaving the general formula (A):

[0003] wherein R₁ is hydrogen, alkyl or aralkyl group and R₂ ishydrogen, are known pharmaceutical active agents. See for example U.S.Pat. No. 4,843,086 and EP 186087 where these and othertetrahydrobenzthiazole derivatives are taught to be useful in treatingschizophrenia, Parkinson's disease or Parkinsonism, and/or hypertension.Among the known compounds is(S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole of the formula(B) which is more commonly known as pramipexole.

[0004] Pramipexole is commercially sold as a dihydrochloride salt in aperoral formulation.

[0005] The compounds of formula (A) have one asymmetric carbon and theymay exist either as a single enantiomer or in a mixed or racemic form.The pharmacological activity of compounds of formula (A) is generallyconnected only or mainly with one isomer thereof. Accordingly,pramipexole is marketed as a single S(−) enantiomer; the dopaminergicactivity of the (S) isomer is twice as high as that of the (R)enantiomer.

[0006] One general process for preparing compounds of the above formula(A) applicable to a synthesis of pramipexole (general method A) issuggested in U.S. Pat. No. 4,843,086, EP 186087 and EP 207696. Theprocess comprises ring halogenation (preferably bromination) of asubstituted aminoketone (C) and the condensation of the so obtainedalpha-halogenaminoketone (D) with thiourea to form a2-aminotetrahydrobenzthiazole ring, as shown in the following scheme:

[0007] In practice, compounds of formula (A) comprising a primary aminogroup or a secondary alkylamino group cannot be prepared from thecorresponding compounds of formula (C) directly due to the reactivity ofthe amino/alkylamino group during preparation, halogenation andcyclization of compounds (C).

[0008] The following three variants of the indirect synthetic processleading to pramipexole, i.e. to a compound of formula (A), wherein R₁ ispropyl and R₂ is hydrogen, may be derived from the above general methodA.

[0009] a) Propylation of a compound (A) wherein both R₁ and R₂ ishydrogen. The starting compound of formula (A), wherein both R₁ and R₂are hydrogen, may be prepared from a compound (C) wherein either R₁ isan amino-protective group such as an acyl or alkoxycarbonyl group and R₂is hydrogen or R₁, —R₂ together form an imino-protective group such asphthalimidogroup; after halogenation and condensation with thiourea, theprotective group is removed in a separate step.

[0010] b) Reduction of a carbonyl moiety in a compound of formula (A)wherein R₁ is a propionyl group and R₁ is hydrogen. A compound offormula (A), wherein R₁ is a propionyl group and R₂ is hydrogen, may beprepared from a compound (C) wherein R₁ is a propionyl group and R₂ ishydrogen.

[0011] c) Bromination and cyclization of a compound (C) wherein R₁ is apropyl group and R₂ is a protective group with subsequent removal of theprotective group by hydrolysis. The starting compound (C) may beprepared from a commercially available p-aminocyclohexanol in threesteps.

[0012] It is apparent that the variant b) is the most straightforwardone for production of pramipexole as it does not require introductionand removal of a protective group; instead, the propionyl group servesas a protective group and it is also a direct precursor for the desiredpropyl group. The corresponding starting compound (C) is however notcommercially available and must be prepared in advance.

[0013] However, the variants of the above general method A prepare onlya racemate. Accordingly, if applied to the synthesis of pramipexole, theabove process yieldsR,S(±)-2-amino-6-propylamino-5,6,7,8-tetrahydrobenzthiazole, which willbe further, whenever appropriate, called “racemic pramipexole.”

[0014] The above-mentioned patents acknowledge that the produced racemiccompound of the general formula (A) may be resolved into singleenantiomers by classical methods such as chromatography on a chiralphase or fractional crystallization of a salt with an optically activeacid. However, even though the S(−) enantiomer of pramipexole wasdisclosed and characterised therein, no information is provided how itwas prepared; i.e., whether it was prepared by a resolution of racemicpramipexole or from some optically active precursor. Further, noinformation is provided on how to produce the S(−) enantiomer ofpramipexole.

[0015] An example of a process for producing optically pure pramipexolewas disclosed later by Schneider and Mierau in J. Med. Chem 30, 494(1987). The authors used the resolution of racemic2,6-diamino-4,5,6,7-tetrahydrobenzthiazole (compound (A), R₁═R₂═H) intoenantiomers by fractional crystallization of salts with L(+) tartaricacid. Following the resolution, the corresponding single enantiomer ofthe resolved diamino-precursor was converted to (−)pramipexole by atwo-step propylation comprising a reaction with propionanhydridefollowed by reduction of the propionyl intermediate.

[0016] In conclusion, the known process for preparing optically purepramipexole by the general method A is the variant a) in the version ofSchneider and Mierau. But, this method suffers from several drawbacksincluding its length and undesirable economics. Thus, there exist a needfor a more straightforward production process leading toS(−)pramipexole.

[0017] Such a more straightforward process may be the variant b) of theabove process; however, it may be commercially interesting only if afeasible process of resolution of the so produced racemic pramipexoleinto (−)pramipexole is found. As of yet, such a process has not beendescribed.

[0018] In ES P200002262, a right of priority therefrom being claimedunder 35 U.S.C. §119 in the present application and the entire contentsof which are incorporated herein by reference, another process isdisclosed for preparing compounds of formula (A) and especiallypramipexole, (general method B), said process being outlined in thefollowing scheme.

[0019] The process comprises selective monobromination of1,4-cyclohexandione (D) in an alcoholic solvent to produce a compound offormula (E) wherein R₃ and R₄ are either the same and each of themrepresents an alkoxy group of 1-4 carbons or they together form a C₂-C₅alkylenedioxy group or an oxo-group; a condensation thereof withthiourea to produce a compound of formula (F) wherein R₃ and R₄ are asdefined above; and a reaction of the compound (F) with a suitable amineunder conditions of reductive amination.

[0020] This general method B allows for the production of pramipexolesubstantially enriched by the desired S(−) enantiomer, e.g. by using achiral catalyst for the reductive amination to propylamine or using achiral amine convertible to propylamine as a reagent in the reductiveamination. However, it would be further desirable to have a method fordirectly improving the optical purity of the resulting pramipexole incase the purity is insufficient.

SUMMARY OF THE INVENTION

[0021] The present invention relates to the resolution of pramipexoleand to the compounds used therein. In particular, one aspect of theinvention relates to a monobasic acid addition salt of2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole, having the generalformula (1)

[0022] wherein X is a monovalent anion derived from an acid. Anotheraspect of the invention relates to a mixed acid addition salt of2-amino-6-propylamino 4,5,6,7-tetrahydrobenzthiazole, having the generalformula (2):

[0023] wherein X is a monovalent anion derived from an acid and Y is ananion derived from an optically active acid.

[0024] Another aspect of the invention relates to a process thatcomprises reacting in a solvent a mixture of (R) and (S) monobasic acidaddition salts of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazolehaving the formula (1)

[0025] wherein X is a monovalent anion derived from an acid, with anoptically active acid to form (R) and (S) diastereomeric mixed saltshaving the formula (2)

[0026] wherein X is a monovalent anion derived from an acid and Y is ananion derived from the optically active acid; and preferentiallyprecipitating one of the (R) and (S) diastereomers from the solvent toform separated optically enriched (R) and (S) diastereomers. Either ofthe enriched diastereomer can be treated with base to form an enrichedand/or pure (R)- or(S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole enantiomer. Theoptically enriched/purified enantiomer can be reacted with an acid toform an acid addition salt. This is especially useful for forming(S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazoledihydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

[0027] Experiments in resolving racemic pramipexole using fractionalcrystallization of diastereomeric salts of pramipexole formed withoptically active acids as suggested in EP 186087 revealed that thedegree of enrichment of the desired enantiomer (optical yield) was lowfor many of the conventional acids; i.e., ditoluyl-D-tartaric,L-mandelic and abietic acid. The resolution of racemic pramipexole intooptical isomers using L(+) tartaric acid and employing “classical”conditions of optical resolution, i.e. treatment of free base of racemicpramipexole with L(+)-tartaric acid in a solvent, precipitation of thetartrate salt and decomposition of the salt, is described in Example 6of ES P200002262. While operable, the optical yield of the product wasstill not ideal for commercial production as several recrystallizationswould be necessary to get the product to the desired optical purity.Specifically, the specific optical rotation of pramipexoledihydrochloride obtained by the above method was [α]_(D)=−48° while thedescribed value of optical rotation of the same product with 99.5%optical purity prepared by the indirect method of Schneider & Mieraushould be [α]_(D)=−65°.

[0028] Moreover, further studies have shown that the procedure islargely inconsistent when repeated and in most solvents the tartratesalt is not formed. Instead, a hemitartrate of pramipexole, i.e. a salthaving 2:1 molar ratio between pramipexole and L-tartaric acid, isformed. After liberation of pramipexole base from such hemitartratesalt, it was found that the product is still essentially a racemate.

[0029] The molecule of pramipexole has two basic nitrogens able to formacid addition salts with optically active acids. Without wishing to bebound, it is theorized that the thiazole-ring nitrogen is the preferredsite to form a cation which is paired with the anion of an opticallyactive acid. Unfortunately, the thiazole nitrogen is situated, inrespect to the chiral carbon, on the opposite side of the molecule. Thechiral centre is probably too distant from the centre of salt formationand, as a result, the produced salts of the respective optical isomersmay have negligible differences in solubility.

[0030] However, it has now been found with surprise that if the racemicpramipexole is first converted into an acid addition salt with oneequivalent of an acid, i.e. into a salt wherein the basicity of onenitrogen is neutralized by an acid (hereinafter “monobasic salt”), suchsalt still may form a mixed salt with an optically active acid and suchmixed salt can exhibit the desired solubility differential between theoptical isomers of pramipexole.

[0031] The structure of the monobasic salts of the present invention isrepresented by general formula (1)

[0032] wherein X is a monovalent anion derived from an acid. The anion Xis derived from an organic or inorganic acid and preferably is derivedfrom a non-optically active acid, especially a non-optically activeorganic acid. Nonetheless, X can be derived from an optically activeacid, especially if the acid does not effectively resolve the resultingdiastereomers. Examples of suitable acids from which X can be derivedinclude hydrochloric, hydrobromic, acetic, benzoic, methane sulfonic,ethane sulfonic, trifluoromethane sulfonic, benzene sulphonic andp-toluene sulfonic acids. Specific examples of monobasic salts of theinvention are pramipexole monohydrochloride, pramipexolemonohydrobromide, pramipexole methanesulfonate, pramipexoletrifluoromethanesulfonate, pramipexole p-toluenesulfonate, andpramipexole benzoate. The asterisk in the formula indicates the chiralcarbon atom. The compounds of formula (1) include individual (R) and (S)enantiomers as well as mixtures thereof. In this regard, thenomenclature (R) and (S) as used throughout herein should be understoodto mean the spatial orientation/configuration of the pramipexole moietythat as a free base or acid addition salt exhibits (+) and (−) opticalrotation, respectively.

[0033] The structure of the mixed salts of the present invention isrepresented by the general formula (2)

[0034] wherein X is as defined above and Y is an anion of an opticallyactive acid. Typically, Y is an anion derived from an acid selected fromthe group consisting of L-tartaric acid, ditoluoyl-D-tartaric acid, anddibenzoyl-D-tartaric acid, although the optically active acids suitablefor use herein are not limited thereto. Specific examples of mixed saltsuseful in the invention include pramipexole monohydrobromidemonotartrate, pramipexole monohydrochloride monotartrate and pramipexolemethanesulfonate dibenzoyl-D-tartrate. X and Y can be the same, but,preferably are different moieties. Like formula (1), the asterisk informula (2) signifies the chiral carbon atom and the formula embracesindividual (R) and (S) forms as well as mixtures thereof. For clarity,while the compounds of formula (2) are diastereomers, the (R) and (S)denotation indicates the stereo configuration of the pramipexole fromwhich the mixed salt was formed. Because Y is derived from an opticallyactive acid, the compounds of formula (2) are diastereomers and as suchcan be separated more easily by physical properties than the underlying(R) and (S) enantiomers themselves. In particular, the diastereomericmixed acid salts are more susceptible to being separated by fractionalcrystallization techniques.

[0035] Accordingly, the present invention provides a process thatcomprises reacting in a solvent a mixture of (R) and (S) monobasic acidaddition salts of the above-formula (1) with an optically active acid toform the corresponding (R) and (S) diastereomeric mixed salts of formula(2) and then preferentially precipitating one of the (R) and (S)diastereomers of formula (2) from the solvent to form separatedoptically enriched (R) and (S) diastereomers of formula (2). The mixtureof (R) and (S) monobasic acid addition salts can be equimolar (50:50) orunequal. In some embodiments the amount of one enantiomer can besignificantly greater than the amount of the other enantiomer,especially if the process is being applied to a recrystallization of aproduct or to a product made by an optically specific method that hasinsufficient purity.

[0036] The optically impure monobasic salt of pramipexole, e.g.pramipexole monohydrochloride, pramipexole monohydrobromide, orpramipexole methanesulfonate, is converted into the mixed salt of theinvention by contacting the salt in a suitable solvent with a suitableoptically active acid, i.e. with the acid suitable to formdiastereomeric pairs of salts with pramipexole, e.g. L-tartaric acid,ditoluoyl-D-tartaric acid, dibenzoyl-D-tartaric acid etc. The solvent ispreferably selected so as to facilitate the salt reaction and to allowsubsequent separation of the resulting diastereomers by fractionalcrystallization. Suitable solvents include methanol, ethanol, acetone,dioxane, ethyl acetate, mixtures thereof, and mixtures of one or more ofthese solvents with water. The temperature of contact is from ambient tothe boiling point of the solvent.

[0037] One of the (R) and (S) diastereomers is preferentiallyprecipitated from the solvent. The precipitation is “preferential” inthat the conditions used allow for one of the diastereomers to beprecipitated to a greater extent than the other. The precipitation maybe spontaneous either during or after the mixed salt-forming reaction,or it may be forced such as by cooling the mixture after contact, addinga contra-solvent, removal of a part of the solvent, or by combination ofthese techniques. In a preferred variant, the mixed salt of the desired(S) isomer of pramipexole is less soluble than that of the (R) isomerand thus the (S) isomer can be preferentially precipitated out of thesolution.

[0038] The obtained solid mixed salt is substantially enriched by oneenantiomer of pramipexole, advantageously by the (S) pramipexole. Asused herein “enrichment” means that the product contains more of one ofthe (R) or (S) diastereomers than the starting diastereomers or startingmonobasic salt. For example, if the monobasic salt contained a 50:50mixture of (R) and (S) enantiomers, then a precipitation of a mixed saltdiastereomer having an (R):(S) ratio of 30:70 would be an enriched (S)diastereomer. The degree of enrichment (optical yield) is typically atleast 75%, more typically at least 80% and preferably is at least 90%.The mother liquor is likewise enriched by a salt of other enantiomer;e.g., (R) pramipexole. Optical yield may be increased byrecrystallization of the desired enriched mixed salt from a suitablesolvent; advantageously using the same solvent as was used for theresolution.

[0039] In an example of the advantageous embodiment of the opticalresolution process of our invention, substantially racemic pramipexolemonohydrochloride reacts with L-tartaric acid in a suitable solventwhereby (S) pramipexole monohydrochloride monotartrate separates outfrom the solution as a solid, while the salt of the (R) enantiomerremains in the solution. Similarly, substantially racemic pramipexolemonohydrobromide reacts with L-tartaric acid in the same type ofsolvent, preferably in methanol, whereby the formed hydrobromidetartrate mixed salt of (S) pramipexole is less soluble and may beisolated as a solid. The (S) mixed salt may be separated from thereaction mixture after precipitation by ordinary methods e.g. byfiltration or centrifugation. The salts may be also isolated in solvatedor hydrated form.

[0040] Alternatively, the mixed salt of the desired (S) isomer can bemore soluble than the (R) isomer in which case the (R) diastereomer ispreferentially precipitated and the (S) diastereomer preferentiallyremains in the solution. This case occurs in preparing mixed salts withdibenzoyl-L-tartaric acid or with di-p-toluoyl-L-tartaric acid. The (S)diastereomer remaining in the solution may be elaborated by evaporationto obtain the desired mixed salt in solid state or may be used as it isin any subsequent process steps. Thus, because both the precipitated andthe remaining dissolved diastereomers are enriched, either theprecipitated or the remaining dissolved form can be used. It ispreferred, however, that the (S) diastereomer be precipitated from thesolvent.

[0041] Monobasic salts of any single optical isomer of pramipexole,particularly (S)-pramipexole, and more particularly (S)-pramipexolemonohydrochloride, monohydrobromide or methane sulfonate as well as themixed salts thereof with an optically active acid, particularly withL(+)tartaric acid, ditoluoyl-D-tartaric acid, dibenzoyl-D-tartaric acidand more particularly (S)-pramipexole monohydrobromide monotartrate, and(S)-pramipexole methanesulfonate dibenzoyl-D-tartrate have not beendisclosed in the prior art and thus they form a specific aspect of thepresent invention. In general mixed salts of formula (2) having apramipexole moiety in the (S) configuration are preferred compounds.Moreover, the optical purity of such compounds is desired to be high,for example at least 75% of the mixed salt material having the (S)pramipexole configuration, more preferably at 80%, more preferably atleast 90%, still more preferably at least 95%, and still more preferablyat least 99% including 99.5% or greater.

[0042] The enriched diastereomer mixed salt, either the precipitate orthe solute, can be neutralized by contacting it with base to liberatethe correspondingly optically enriched pramipexole. The enriched mixedsalt may be advantageously isolated from the reaction mixture andoptionally (re)crystallized before being contacted with base. Generally,the liberation of the desired enantiomer of pramipexole from theenriched mixed salt proceeds by contacting the salt with an equivalentof a suitable base, e.g., metal hydroxides, in a proper solvent,advantageously in water. The so formed free base of the pramipexole isisolated by ordinary methods. If water has been employed as a solventfor neutralization, (S)-pramipexole precipitates as a solid and isisolated by filtration or centrifugation. Alternately, for example indecomposition of (S)-pramipexole methane sulfonate dibenzoyl-D-tartrate,the mixed salt is contacted with water, then acidified with a strongeracid, e.g. with hydrochloric acid, and the liberated resolution agent isremoved by extraction with an organic solvent e.g. with ethylacetate.(S)-Pramipexole is liberated from the aqueous layer by alkalinisationwith sodium hydroxide solution. Any conventional method applicable todecomposition of pramipexole salt and liberation of pramipexole base maybe employed. Advantageously, such methods are allow the isolation of,and, if advantageous, the reprocessing of the resolution agent.

[0043] The formed free base of pramipexole, especially the enriched (S)enantiomer may be further converted into an acid addition salt with asuitable acid, particularly with a pharmaceutically acceptable acid bymethods known per se. In particular, the formed free base of(S)-pramipexole may be converted into pramipexole dihydrochloride.

[0044] If the optical purity of the obtained pramipexole product is notsufficient, the process may be repeated. Similarly, the process may beapplied to pramipexole products from a synthesis which areinsufficiently pure (S)-pramipexole. In either case, the productenriched with (S)-pramipexole is accordingly converted to a monobasicsalt of formula (1), treated with an optically active acid in a suitablesolvent to form diastereomeric mixed salts of formula (2), fractionallycrystallizing to obtain an enriched diastereomer, and liberating theoptically pure product from the desired fraction of the mixed salt.

[0045] A preferred form of the process of the present inventioncomprises the steps of

[0046] forming a monobasic salt of formula (I) by contacting racemicpramipexole with an equivalent of an acid in a solvent

[0047] contacting the monobasic salt with an optically active acid in asolvent to form a mixed salt of the general formula (2)

[0048] fractional crystallization of the mixed salt to yield a mixedsalt substantially enriched by one optical isomer of pramipexole

[0049] liberation of pramipexole substantially enriched by one opticalisomer of pramipexole by decomposition of the said enriched salt and,optionally,

[0050] converting the optically enriched pramipexole into an acidaddition salt.

[0051] Preferably, the resulted enriched pramipexole is pramipexoleenriched by the (S)-isomer.

[0052] The salt of undesired (R) pramipexole, either in a solution or asa solid, still represents a valuable material; it may be converted to aracemic pramipexole which may serve as a substrate for next resolutionprocess by any suitable process of racemization. This way, overalllosses of produced pramipexole are minimised.

[0053] The starting racemic or mixed (R,S)-pramipexole for theresolution process of the invention may be prepared by any processincluding the cited general methods above. Particularly suitable areprocesses based on the following schemes:

[0054] a) In a first method, racemic pramipexole is produced by abromination of 4-propionylaminocyclohexanol followed by the condensationwith thiourea according to a general method of EP 186087. The propionylgroup is then reduced to propyl group by a suitable reduction agent,e.g. by in situ formed borane.

[0055] b) In a second method,2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole is prepared by amonobromination of 1,4-cyclohexanone in methanol followed by thecondensation with thiourea in situ. The 6-oxo intermediate reacts withpropylamine under presence of a reducing agent, e.g. sodiumcyanoborohydride.

[0056] Racemic or enriched pramipexole may be isolated from the reactionmixture as a free base and contacted with an equivalent of suitable acidin a suitable solvent to form a monobasic salt of formula (1) or it maybe directly converted into a monobasic salt of the invention in thereaction mixture by treatment of the reaction mixture with a suitableacid. The monobasic salts may be used in the process of the inventionwithout isolation from the reaction mixture or, preferably, they may beisolated in a solid state, optionally in solvated or hydrated form, byconventional techniques of precipitation or crystallization followed byfiltration or centrifugation. In an advantageous embodiment of theprocess of the invention, the formed monobasic salt is isolated from thereaction mixture in a solid state prior to the contact with theoptically active acid, and it may be advantageously purified, e.g. byrecrystallization before being further reacted.

[0057] Optically pure or substantially pure (S) pramipexole, acidaddition salts thereof and particularly pramipexole dihydrochlorideprepared by the process of the invention are useful in the preparationof medicaments for treatment of various diseases or conditions includingschizophrenia, Parkinson's disease, Parkinsonism, hypertension, anddepressions among others. It may be used alone or in combination withergot preparation (e.g. brompcryptine or pergolide) or with levodopa.Such medicaments may be formulated for peroral, transdermal orparenteral application, for instance in a form of tablets or capsules.The formulations comprise therapeutically effective amounts of theactive substance together with a pharmaceutically acceptable carriers ordiluents and may be prepared by any conventional method.

[0058] An advantageous dosage form for peroral application ofpramipexole prepared by the process of the invention is a tablet.Suitable tablets comprise from 0.1 to 5 mg of pramipexoledihydrochloride monohydrate, advantageously 0.125, 0.25, 0.5, 1.0, and1.5 mg. Suitable excipients in the tablet comprise mannitol, maizestarch, povidone.

[0059] Composition of tablets for peroral application of pramipexole maybe as follows: Pramipexole  0.088 mg  0.18 mg   0.7 mg  0.88 mg (as afree base) Mannitol 49.455 mg  61.0 mg 121.50 mg 162.0 mg Magnesiumstearate  1.230 mg  1.50 mg   3.0 mg  4.0 mg Maize starch 25.010 mg30.90 mg  61.85 mg 82.55 mg Maize starch  7.300 mg  9.0 mg  18.00 mg 24.0 mg Colloid silicon dioxide  0.940 mg  1.20 mg  2.30 mg  3.10 mgPovidone  0.940 mg  1.15 mg  2.35 mg  3.10 mg

[0060] Suitable tablet production methods comprise wet granulationmethods. The tablets should be advantageously packed into light- andhumidity protective blisters.

[0061] Controlled release compositions may be produced using pramipexoleprepared by the process of the invention. In a suitable arrangement, asalt of pramipexole may be formulated into controlled-release pellets ortablet formulation, such formulation comprising a mixture of apramipexole salt, a suitable filler, e.g. microcrystalline cellulose,and a suitable release controlling agent comprising water and/or awater-insoluble macromolecular substance such as an acrylate polymer ora modified cellulose.

[0062] The present invention is more particularly described andexplained by the following examples. It is to be understood, however,that the present invention is not limited to these examples and variouschanges and modifications may be made without departing from the scopeof the present invention.

EXAMPLES

[0063] Preparation 1: Racemic Pramipexole from2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole (General Method B)

[0064] 10 g of 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazolehydrobromide was added to the mixture of 5 mL of propylamine and 125 mLof methanol under nitrogen. The mixture was stirred for 20 minutes. Then2.7 g of sodium cyanoborohydride was added in parts during 30 minutes.The solution was acidified with 2 mL of acetic acid to the value pH=7-8.Reaction mixture was worked up after 20 hours of stirring by addition of8 mL of HCl. Precipitated solid was removed by suction and the filtratewas evaporated to dryness. The solid residue was heated at reflux with250 mL of ethanol for 20 minutes. Undissolved part was filtered off andthe hot filtrate was concentrated under reduced pressure and cooled onan ice bath. Precipitated crystals were removed by suction and the cakewas washed with cold ethanol to give 5.1 g of a product with m.p.245-257° C.

[0065] The solid product was dissolved in 28 mL of water and thesolution was alkalinized with 25% aqueous NaOH. The mixture was stirredfor 2 hours and precipitated crystals were removed by suction and washedwith water to give 2.7 g of the title product with m.p. 147-149° C.

[0066] Preparation 2: Racemic Pramipexole from(±)-2-amino-6-propanamido-4,5,6,7-tetrahydrobenzthiazole (General MethodA)

[0067] 6.4 g of sodium borohydride was mixed with 30 mL of anhydroustetrahydrofuran under nitrogen. The suspension was cooled at 0-5° C. and5.4 g of (±)-2-aminopropanamido-4,5,6,7-tetrahydrobenzothiazole wasadded to this suspension. 21 mL of boron trifluoride diethyl etheratewas dropwise added to the suspension at 0-5° C. during 1.5 hour. Thereaction mixture was gently warmed to 20° C. during one hour. Reactionmixture was heated at 48-50° C. for 4 hours. Then it was cooled to 0-5°C. and 50 g ice was added followed by addition of 69 mL of 36%hydrochloric acid. The reaction temperature was kept below 10° C. for 60minutes. Then solvent was removed in vacuo and the residue was dissolvedin 300 mL of water. Water solution was alkalinized by addition of 25%sodium hydroxide solution. Precipitated substance was collected byfiltration, washed with water and air-dried to give 4.4 g of product.The yield 87%, m.p. 146-160° C.

Example 1 Resolution of (±)-Pramipexole via PramipexoleMonohydrochloride L-Tartrate

[0068] a) Preparation of(±)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazoleMonohydrochloride (Pramipexole Monohydrochloride)

[0069] 4.2 g of (±)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazolewas dissolved in 15 mL of hot methanol and 1.65 mL of 36% hydrochloricacid was added. The obtained suspension was stirred, cooled andprecipitated solid was filtered off. The cake was washed with coldmethanol and air-dried to give 4.2 g of product with m.p. 273-282° C.

[0070] b) A Mixed Salt of Pramipexole Monohydrochloride WithL(+)Tartaric Acid

[0071] 3.00 g of (±) 2-aminopropylamino-4,5,6,7-tetrahydrobenzthiazolemonohydrochloride was dissolved in 23 mL of hot methanol and 1.80 g ofL(+)tartaric acid was added. White crystals precipitated, the mixturewas cooled and crystals were removed by suction, washed with coldmethanol and dried to give 2.8 g of pramipexole monohydrochloridemonotartrate which was recrystallized from hot methanol to give 2.2 g ofsalt with m.p. 203-219° C.

[0072] c) Liberation of (S)-Pramipexole Free Base

[0073] Pramipexole monohydrochloride monotartrate from the step b) wasdissolved in 10 mL of water, the solution was cooled to 10° C., andsolution of 5 g of potassium hydroxide in 10 mL of water was added. Awhite precipitate was formed. The mixture was stirred at 10° C. for 30minutes and the white crystals were removed by filtration and washedwith cold water. The cake was dried to give 0.95 g of the whitecrystals.

[0074] d) (S)-Pramipexole Dihydrochloride

[0075] The crystals from the step c) were dissolved in 7 ml of ethanoland gaseous hydrogen chloride was bubbled through the solution. Themixture was stirred at 10° C. for 1 hr and the formed white crystalswere removed by filtration and washed with cold methanol. The cake wasdried to give 1.1 g of white crystals with m.p. 274-284° C. and[α]_(D)=−66.5° (c=1, MeOH).

Example 2 Resolution of (±)Pramipexole via Pramipexole MonohydrobromideL-Tartrate

[0076] a) Preparation of(±)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazoleMonohydrobromide (Pramipexole Monohydrobromide)

[0077] 4.00 g of (±)-2-aminopropylamino-4,5,6,7-tetrahydrobenzothiazolewas dissolved in 10 mL of hot methanol and 2.2 mL of 48% hydrobromicacid was added. The obtained suspension was stirred, cooled andprecipitated solid was filtered off. The cake was washed with coldmethanol and air-dried to give 2.7 g of(±)-2-aminopropylamino-4,5,6,7-tetrahydrobenzothiazole monohydrobromidewith m.p. 236-245° C.

[0078] b) A Mixed Salt of Pramipexole Hydrobromide With L(+)TartaricAcid

[0079] 2.00 g of (±) 2-aminopropylamino-5,6,7,8-tetrahydrobenzothiazolemono-hydrobromide was dissolved in 20 mL of hot methanol-water mixture(100:5 v/v) and 1.02 g of L-(+)tartaric acid was added. White crystalsprecipitated, the mixture was cooled and crystals were removed bysuction, washed with cold methanol and dried to give 0.65 g ofpramipexole monohydrobromide monotartrate which was recrystallized fromhot methanol to give 0.44 g of salt with m.p. 210-216° C.

[0080] c) Liberation of (S)-Pramipexole Free Base

[0081] 0.40 g of the salt from the step b) was dissolved in 8 mL ofwater, the solution was cooled to 10° C., and 25% aqueous sodiumhydroxide was added. A white precipitate was formed. The mixture wasstirred at 10° C. for 30 minutes and the white crystals were removed byfiltration and washed with cold water. The cake was dried to give 0.22 gof the white crystals m.p. 136-141° C.

[0082] d) (S)-Pramipexole Dihydrochloride

[0083] These crystals were dissolved in 2 ml of ethanol and gaseoushydrogen chloride was bubbled through the solution. The mixture wasstirred at 10° C. for 1 hr and the white crystals were removed byfiltration and washed with cold methanol. The cake was dried to give0.34 g of white crystals with m.p. 276-285° C. and [α]_(D)=−62.3° (inmethanol)

Example 3 Resolution of (±) Pramipexole via Pramipexole MethanesulfonateDibenzoyl-D-tartrate

[0084] a) Preparation of(±)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazoleMonomethanesulfonate (Pramipexole Monomethanesulfonate)

[0085] 11.0 g of (±)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole was dissolved in180 mL of hot isopropanol and 3.8 mL of methanesulfonic acid was added.The formed precipitate was filtered off after cooling and dried to give10.2 g of crystals with m.p. 227-237° C.

[0086] b) A Mixed Salt of Pramipexole Monomethanesulfonate WithDibenzoyl-D-tartaric Acid

[0087] 5 g of (±) 2-aminopropylamino-4,5,6,7-tetrahydrobenzothiazolemono-methanesulfonate was dissolved in a hot mixture of 45 mL ofmethanol and 5 mL of water. Then 6.0 g of dibenzoyl-D-tartaric acid wasadded under stirring and the mixture was cooled to ambient temperature.Precipitate of crystals was removed by suction, recrystallized frommethanol and dried to give 4.2 g of the product with m.p. 177-181° C.

[0088] c) (S)-pramipexole Free Base

[0089] The compound from the previous step was dissolved in the mixtureof 30 mL of ethyl acetate, 30 mL of water and 5 mL of 36% hydrochloricacid Water layer was twice extracted with 10 mL of ethylacetate and thenit was alkalinized with sodium hydroxide solution. Precipitate wasremoved by suction and washed with water to give 2.50 g of the whitecrystals with m.p. 276-285° C. and [α]_(D)=−62.3° (in methanol)

Example 4 Resolution of (±) Pramipexole via Pramipexole MethanesulfonateDitoluyl-D-tartrate

[0090] a) A Mixed Salt of Pramipexole Monomethanesulfonate WithDitoluoyl D-Tartaric Acid

[0091] 3.6 g of pramipexole monomethanesulfonate was dissolved in a hotmixture of 30 mL of methanol and 10 mL of water. Then 3.77 g of ditoluoyl-D-tartaric acid was added under stirring and the mixture wascooled to ambient temperature. Precipitate of crystals was removed bysuction and dried. Yield: 4.2 g, m.p. 180-184° C.

[0092] b) (S)-Pramipexole Free Base

[0093] The compound from the step a) was dissolved in the mixture of 30mL of ethylacetate, 30 mL of water and 5 mL of 36% hydrochloric acid.Water layer was twice extracted with 10 mL of ethyl acetate and then itwas alkalinized with sodium hydroxide solution. Precipitate was removedby suction and washed with water. (S)-Pramipexole with optical yield 48%was obtained.

[0094] The invention having been thus described, it will be readilyapparent to those skilled in the art that further changes andmodifications in actual implementation of the concepts and embodimentsdescribed herein can easily be made or may be learned by practice of theinvention, without departing from the spirit and scope of the inventionas defined by the following claims.

I claim:
 1. A monobasic acid addition salt of2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole, having the generalformula (I)

wherein X is a monovalent anion derived from an acid.
 2. The saltaccording to claim 1, wherein the anion X is derived from an acidselected from the group consisting of hydrochloric, hydrobromic,hydroiodic, nitric, benzoic, acetic, methane sulfonic, ethane sulfonic,trifluoromethane sulfonic, benzene sulfonic, and p-toluene sulfonicacids.
 3. The salt according to claim 1 wherein X is a chloride anion, abromide anion, or a methane sulfonate anion.
 4. A mixed acid additionsalt of 2-amino-6-propylamino 4,5,6,7-tetrahydrobenzthiazole, having thegeneral formula (2):

wherein X is a monovalent anion derived from an acid and Y is an anionderived from an optically active acid.
 5. The mixed salt according toclaim 4, wherein Y is an anion derived from an acid selected from thegroup consisting of L-tartaric acid, ditoluoyl-D-tartaric acid, anddibenzoyl-D-tartaric acid.
 6. The mixed salt according to claim 4 whichis 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazolemonohydrochloride monotartrate,2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrobromidemonotartrate, or 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazolemonomethanesulfonate dibenzoyl-D-tartrate.
 7. The mixed salt accordingto claim 4, wherein at least 80% of the2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole moiety is in the(S) configuration.
 8. A process which comprises: reacting in a solvent amixture of (R) and (S) monobasic acid addition salts of2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole having the formula(1)

wherein X is a monovalent anion derived from an acid, with an opticallyactive acid to form (R) and (S) diastereomeric mixed salts having theformula (2)

wherein X is a monovalent anion derived from an acid and Y is an anionderived from said optically active acid; and preferentiallyprecipitating one of said (R) and (S) diastereomers from the solvent toform separated optically enriched (R) and (S) diastereomers.
 9. Theprocess according to claim 8, wherein said precipitation occursspontaneously during or after said reaction.
 10. The process accordingto claim 8, wherein said precipitation is induced by reducing thetemperature of the solvent.
 11. The process according to claim 8,wherein said solvent is selected from the group consisting of methanol,ethanol, acetone, dioxane, ethyl acetate, mixtures thereof, and mixturesof one or more with water.
 12. The process according to claim 8, whereinsaid mixture of (R) and (S) monobasic salts of formula (1) are selectedfrom the group consisting of2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrochloride,2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrobromide,and 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazolemonomethanesulfonate.
 13. The process according to claim 8, wherein saiddiastereomeric mixed salts of formula (2) are selected from the groupconsisting of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazolemonohydrochloride monotartrate,2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrobromidemonotartrate, and 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazolemonomethanesulfonate dibenzoyl-D-tartrate.
 14. The process according toclaim 8, which further comprises treating one of said optically enricheddiastereomers with base to form the corresponding optically enriched (R)or (S) 2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole.
 15. The processaccording to claim 14, wherein said precipitated optically enricheddiastereomer is treated with said base.
 16. The process according toclaim 15, which further comprises isolating said precipitated opticallyenriched diastereomer and dissolving said isolated diastereomer in asecond solvent before or during treating with said base.
 17. The processaccording to claim 16, wherein said second solvent is water.
 18. Theprocess according to claim 15, wherein the (S) diastereomer ispreferentially precipitated from said solvent and is treated with saidbase to form optically enriched(S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole.
 19. The processaccording to claim 18, wherein said enriched(S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole has an opticalpurity of at least 98%.
 20. The process according to claim 14, whichfurther comprises reacting said enriched (R)- or(S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole with an acid to formthe corresponding enriched (R)- or(S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole acid addition salt.21. The process according to claim 19, which further comprises reactingsaid enriched (S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole withhydrochloric acid to form(S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzthiazole dihydrochloride. 22.The process according to claim 8, wherein said mixture does not containan equal amount of (R) and (S) monobasic salts.